Pulmonary Allergy Drugs Advisory Committee Meeting

1
Pulmonary - Allergy Drugs Advisory Committee
Meeting

• January 17, 2002
• FLOVENT DISKUS NDA 20-833
• ADVAIR DISKUS NDA 21-077

2
FLOVENT DISKUS and ADVAIR DISKUS

• David Wheadon, MD
• Senior Vice President, Regulatory Affairs
• GlaxoSmithKline

3
sNDAs forFLOVENT DISKUS and ADVAIR DISKUS

• INDICATION
• Long term, twice-daily maintenance treatment of
  Chronic Obstructive Pulmonary Disease (including
  emphysema and chronic bronchitis)

4
SEREVENT(salmeterol xinafoate)

• Serevent Inhalation Aerosol approved for COPD,
  1998
• Approval sought for Serevent Diskus for the
  maintenance treatment of bronchospasm associated
  with COPD

5
FLOVENT(fluticasone propionate)

• Currently Approved in US for maintenance
  treatment of asthma
• Approved for COPD in 67 countries outside US
• Worldwide exposure estimate - 14.4 million
  patient years
• Approval sought for Flovent Diskus for
  maintenance treatment of COPD at doses of 250mcg
  and 500mcg BID

6
ADVAIR DISKUS(fluticasone propionate
andsalmeterol inhalation powder)

• Currently approved for maintenance treatment of
  asthma
• Worldwide exposure estimate - 1.4 million patient
  years
• Approval sought for maintenance treatment of COPD
  at doses of 250/50mcg and 500/50mcg BID

7
Impact of COPD in the US

• Affects an estimated 21.7 million Americans1
• 6.5 Million Diagnosed
• 4.3 Million Treated With Prescription Medications
• The fourth leading cause of death2
• 114,000 deaths in 19982
• Third leading cause of death by 20203
• Annual cost gt30 billion2
• 14.7 billion in direct healthcare costs
• 15.7 billion in indirect healthcare costs

1Data on file (analysis of NHANES III data),
GlaxoSmithKline. 2National Center for Health
Statistics, National Health Interview Survey,
1998. Information cited in American Lung
Association, trends in Chronic bronchitis and
Emphysema Morbidity and Mortality, December,
2000. 3Murray CJL and Lopez AD, eds. The Global
Burden of Disease. Vol. 1. 1996362.
8
Global Initiative for ChronicObstructiveLungDis
ease
Global Initiative for Chronic Obstructive Lung
Disease. Global Strategy for the Diagnosis,
Management, and Prevention of Chronic Obstructive
Pulmonary Disease NHLBI/WHO Workshop Report.
Bethesda, Md National Heart, Lung, and Blood
Institute, National Institutes of Health March
2001. NIH publication 2701A.
9
Clinical Effects of ICS in COPD

• Reference N Duration Treatment/Day Outcome
• Nishimura et al., 1999 30 4 w BDP 3000mcg ? FEV1,
  ? Sx
• OBrien et al., 2001 24 6 w BDP 1500mcg FEV1
  preserved
• Thompson et al., 1992 30 6 w BDP 1000mcg ? FEV1,
  ? bronchitis
• Weiner et al., 1995 30 6 w BUD 800mcg ? FEV1, ?
  prn med
• Weiner et al., 1999 168 6 w BUD 1600mcg ? FEV1, ?
  prn med
• Auffarth et al., 1991 21 8 w BUD 1600mcg ?
  dyspnea
• Kerstjens et al., 1993 39 12 w BDP 800mcg ? FEV1
• Dompeling et al., 1992 28 52 w BDP 800mcg ? PEF,
  ? Sx
• Paggiaro et al., 1998 281 24 w FP 1000mcg ?
  FEV1, ? exac
• ISOLDE, 2000 751 3 Y FP 1000mcg ? FEV1, ? QoL, ?
  exac
• Euroscope, 1999 1277 3 Y BUD 800mcg ? FEV1, ?
  exac
• Lung Health II, 2000 1116 3 Y TAA 1200mcg ? Sx ,
  ? exac
• Sin Tu, 2001 22620 Varied ? morbidity,
  mortality

10
Current Use of ICS for COPDPrescription Data
from July 2001

• 40 of all COPD patients were prescribed ICS
  therapy
• 46 of all patients prescribed 2 or more COPD
  maintenance medications (any medication other
  than albuterol)
• 72 prescribed an ICS
• 57 prescribed an ICS a maintenance
  bronchodilator
• 17 prescribed Advair

Source NDC Health, July 2001
11
SUMMARY

• COPD is a serious public health issue
• Considerable unmet medical needs
• New treatment options are needed

12
Order of GSK Presentation

• Scientific and Clinical Rationale
• Dr. Malcolm Johnson (15 minutes)
• Clinicians Perspective
• Dr. James Donohue (15 minutes)
• Clinical Efficacy and Safety
• Dr. Tushar Shah (45 minutes)
• Conclusion and Q A
• Dr. David Wheadon

13
(No Transcript)
14
Scientific and Clinical Rationale

• Malcolm Johnson, PhD
• Global Director of Respiratory Science
• GlaxoSmithKline

15
Pathology of COPD
Inflammation
Structural Changes
AirwayObstruction
16
Pathophysiological Features of COPD
Airway Obstruction
StructuralChanges
Inflammation
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis
Symptoms ? FEV1 Exacerbations
17
Inhaled Corticosteroids

• Do inhaled corticosteroids reduce inflammation in
  COPD?
• Are inhaled corticosteroids effective treatment
  for COPD?

18
Anti-Inflammatory Effects of ICS in COPD

• Reference N Duration Treatment/Day Outcome
• Balbi 8 6 w BDP 1500mcg ? BAL neutrophils, IL-8
  et al., 2000 and MPO
• Confalonieri 24 8 w BDP 1500mcg ? Sputum
  neutrophils et al., 1998
• Llewellyn-Jones 17 8 w FP 1500mcg ? Sputum
  neutrophil et al., 1996 chemotactic
  activity
• Thompson 30 6 w BDP 1000mcg Improvement in
  bronchial et al., 1992 cell counts and
  epithelial lining fluid proteins
• Yildiz 18 8 w FP 1500mcg ? Sputum neutrophilset
  al., 2000
• Hattotuwa 37 12 w FP 1000mcg ? Biopsy CD8/CD4
  et al., 1999, 2000 Tcell ratio and mast cells
• Verhoeven 20 24 w FP 1000mcg ? Biopsy CD8 Tcells
  and et al., 1999 eosinophils
• Keatings 13 2 w BUD 1600mcg No change in total
  and et al.,1996 differential cell counts or
  TNF?, ECP, EPO and MPO
• Culpitt 13 4 w FP 1000mcg No change in sputum et
  al., 1999 neutrophils, IL-8 or SLPI
• OBrien 5 6 w BDP 400mcg No change in sputum et
  al., 2001 neutrophils

19
Fluticasone Propionate Reduces Total Cell Counts
and Neutrophils in the Sputum of COPD Patients
Total Cell Counts
Neutrophils

x106 cells/g

percent
Placebo
FP 1500 mcg/day

Plt0.05
Yildiz et al. Respiration. 2000 6771-76.
20
ICS (FP) Reduces Inflammation in COPD
Airway Obstruction
StructuralChanges
Inflammation
ICS (FP) Positive Effect
?
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis
Symptoms ? FEV1 Exacerbations
21
Inhaled Corticosteroids

• Do inhaled corticosteroids reduce inflammation in
  COPD?
• Are inhaled corticosteroids effective treatment
  for COPD?

22
Clinical Effects of ICS in COPD

• Reference N Duration Treatment/Day Outcome
• Nishimura et al., 1999 30 4 w BDP 3000mcg ? FEV1,
  ? Sx
• OBrien et al., 2001 24 6 w BDP 1500mcg FEV1
  preserved
• Thompson et al., 1992 30 6 w BDP 1000mcg ? FEV1,
  ? bronchitis
• Weiner et al., 1995 30 6 w BUD 800mcg ? FEV1, ?
  prn med
• Weiner et al., 1999 168 6 w BUD 1600mcg ? FEV1, ?
  prn med
• Auffarth et al., 1991 21 8 w BUD 1600mcg ?
  dyspnea
• Kerstjens et al., 1993 39 12 w BDP 800mcg ? FEV1
• Dompeling et al., 1992 28 52 w BDP 800mcg ? PEF,
  ? Sx
• Paggiaro et al., 1998 281 24 w FP 1000mcg ?
  FEV1, ? exac
• ISOLDE, 2000 751 3 Y FP 1000mcg ? FEV1, ? QoL, ?
  exac
• Euroscope, 1999 1277 3 Y BUD 800mcg ? FEV1, ?
  exac
• Lung Health II, 2000 1116 3 Y TAA 1200mcg ? Sx ,
  ? exac
• Sin Tu, 2001 22620 Varied ? morbidity,
  mortality
• Keatings et al., 1999 13 2 w BUD 1600mcg No
  ? PFT, Sx, prn med
• Culpitt et al., 1999 13 4 w FP 1000mcg No ?
  PFT, Sx
• Engel et al., 1989 18 12 w BUD 800mcg No ?
  PFT, SxWatson et al., 1992 14 12 w BUD
  1200mcg No ? PFT, Sx
• Bourbeau et al., 1998 79 28 w BUD 1600mcg No
  ? PFT, Sx, QoL

23
Reduced Risk of Mortality and Repeat
Hospitalization with Inhaled Corticosteroids
Adapted from Sin DD, Tu JV. Am J Respir Crit
Care Med 2001164580-584
24
Fluticasone Propionate Significantly Improves
Pre-dose FEV1 in COPD
Plt0.01
Plt0.02
? FEV1 (L)
Week
Paggiaro et al. Lancet. 1998 351773-780.
25
Collection of Exacerbation Data in Paggiaro et
al., 1998

• Exacerbation history at least 1/ year (treated
  by physician or hospital) for previous 3 years
• Exacerbation worsening of COPD symptoms
  requiring changes to normal treatment
• Exacerbation severity
• Mild patient self-managed at home
• Moderate patient treated by a physician
• Severe patient hospitalized
• Multiple exacerbations requiring OCS were allowed

Paggiaro et al. Lancet. 1998 351773-780.
26
Fluticasone Propionate Reduces Moderate/Severe
Exacerbations in COPD
Treatment Group
Fluticasone Placebo propionate (n139) (n142)
Number of exacerbations Total 111 76 Number of
Patients with one or moreexacerbations Total
51 45 Mild 7 (14) 17 (38) Moderate/severe 44
(86) 27 (60)
Each patient may have experienced more than one
exacerbation. plt0.001.
Paggiaro et al. Lancet. 1998 351773-780.
27
Inhaled Steroids in Obstructive Lung Disease in
Europe (ISOLDE)
FP MDI 500mcg BID
Corticosteroid Withdrawal
PlaceboRun-in
Placebo BID
2 Months
3 yrs
N 751 Reversibility lt10 predicted Mean FEV1
50 at baseline
Burge PS et al. Br Med J. 20003201297-1303.
28
FP Improves Post-bronchodilator FEV1 Response in
COPD ISOLDE Study
Adapted from Burge PS et al. Br Med J.
20003201297-1303.
29
FP Reduces Median Annual Exacerbation Rate
ISOLDE Study
1.32
p0.026
O.99
Exacerbations/patient/year
Burge PS et al., Br Med J. 20003201297-1303
30
FP Slows the Decline in Quality of Life as
Measured by SGRQ ISOLDE Study
An increase in score reflects a decrease in
quality of life. St Georges Respiratory
Questionnaire Burge PS et al. Br Med J.
20003201297-1303.
31
ICS (FP) Reduces Inflammation in COPD
Airway Obstruction
StructuralChanges
Inflammation
ICS (FP) Positive Effect
?
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis
? Symptoms ? FEV1 ? Exacerbations
32
Salmeterol in COPD
33
Salmeterol is a Long-Acting Bronchodilator in COPD
P lt .001 salmeterol vs placebo. Adapted from
Mahler DA et al. Chest. 1999115957-965.
34
Salmeterol Reduces Airway Obstruction in COPD
Airway Obstruction
StructuralChanges
Inflammation
Salmeterol Positive Effect
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis

• Symptoms
• ? FEV1
• Exacerbations

35
Combined Effects of Salmeterol and FP in COPD
Salmeterol FP
?
Airway Obstruction
StructuralChanges
Inflammation
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis

• ? Symptoms
• ? FEV1
• ? Exacerbations

36
Corticosteroids Increase RespiratoryMucosal
Beta2-receptors

0.45
0.40
0.35
0.30
beta2-receptor/actin ratio
0.25
0.20
0.15
0.10
plt0.04

0.05
0
Baseline
BDP 100mcg for 3 days
Baraniuk et al AJRCCM 155 704-710(1997)
37
Salmeterol Potentiates the Effect of FP on
TNF?-induced IL8 Release fromAirway Smooth
Muscle Cells
IL8 (pg/ml)
P lt0.01
?
(0.1 µM)
(1 µM)
(0.1 µM)
Adapted from Pang L, and Knox AJ. Am J Respir
Cell Mol Biol. 2000 23 79-85.
38
Rationale for CombiningFP with Salmeterol

• Fluticasone propionate is an effective inhaled
  anti-inflammatory corticosteroid with clinical
  benefit in COPD.
• Salmeterol is a long-acting b2-adrenoceptor
  agonist with demonstrated efficacy in COPD.
• Each molecule influences a different aspect of
  COPD pathophysiology, so together they provide a
  broad therapeutic cover.
• There is some evidence of interaction between
  these molecules which may be important in
  improving the overall efficacy of the combination.

39
(No Transcript)
40
Clinicians Perspective

• James F. Donohue, MD
• Chief, Pulmonary and Critical Care
  MedicineUniversity of North Carolina, Chapel Hill

41
Overview

• Diagnosis of COPD
• Evaluating treatment effects in COPD
• FEV1
• Other measures
• GOLD guidelines
• Clinicians Perspective

42
Diagnosis of COPD

• Clinically based on
• Smoking history
• Age
• Symptoms
• Persistent airflow obstruction (spirometry)
• FEV1 post bronchodilator lt 80 predicted
• FEV1 / FVC lt 70
• The presence of reversibility does not exclude a
  diagnosis of COPD

43
Bronchodilator Response in COPDIntermittent
Positive Pressure Breathing Trial (IPPB)

• Evaluated the BD response to inhaled
  isoproteronol in 985 subjects with COPD (asthma
  excluded)
• Pre and post- bronchodilator FEV1 evaluated every
  3 months for 3 yrs.
• Key demographics
• Age 60.9
• Male 79
• Smoking Status
• 54 pack yrs
• 40 current smokers
• FEV1 ( predicted) 36

Anthonisen, et al. Am Rev Respir Dis,
198613314-20.
44
Bronchodilator Response in COPD IPPB Trial

• Approximately half of the subjects were
  reversible at screening (gt12 increase in FEV1
  over baseline)
• In subjects non-reversible at screening (lt10
  increase in FEV1)
• 30 of these subjects had a gt15 increase in FEV1
  at each subsequent test day
• 68 of these subjects had a gt15 increase in FEV1
  on at least one of the 7 follow-up test days

Annals of Internal Medicine, 198399612-620.
Anthonisen, et al. Am Rev Respir Dis,
1986133814-819.
45
Demographic and Reversibility Data from Clinical
Trials in COPD

• Salmeterol Combivent Formoterol
• (n816) (n1067) (n780)
• Age 63 64 63
• male 68 69 75
• Pack yr 63 na 42
• FEV1 L ( pred) 1.25 (40) 0.99 (36) 1.3 (45)
• Pts Rev 62 68-73 42

Data on file SLGA 4004, SLGA 4005, Chest 1994
1051411-1419. Chest 1999 115966-971. Am J
Respir Crit Care Med. Vol 165. p. 778-784, 2001.
46
Efficacy Measures Used to Assess Treatment
Response in COPD

• Spirometry (FEV1)
• Objective, reproducible
• Diagnostic and prognostic
• Other Measures
• Health Status (QOL)
• Symptoms
• Exacerbations

47
FEV1 Response withCombivent on Day 85
Ipratropium Albuterol (n 173)Albuterol (n
165)Ipratropium (n 176)
? FEV1 ()
Postdose (hours)
Combivent is a registered trademark of Boehringer
Ingelheim.Bone R et al. Chest.
19941051411-1419.
48
Other Efficacy Measures Observed with Combivent

• Ipratropium Albuterol Ipratropium Albuterol
• Measure (n173) (n176) (n165)
• CRDQ (QOL) ns ns ns
• Physician Global ns ns ns Evaluation
• Symptom Score ns ns ns
• PEFR ns ns ns

ns not significant compared to baseline and/or
components CRDQ Chronic Respiratory Index
Questionnaire
Bone R et al. Chest. 19941051411-1419.
49
Other Efficacy Measures Observed with Serevent MDI

• Rennard et al. Mahler et al.Measure
  (n405) (n411)
• PEF ? ?
• NT Awakenings ? ?
• Ventolin use ? ?
• TDI (Dyspnea)
• CRDQ
• Diary Symptoms
• Borg Dyspnea
• Six min walk
• COPD exac. ( pts)
• Time to first exac. ?

? p0.05 salmeterol vs. placebo
pgt0.05 salmeterol vs. placebo
Am. J. Respir. Crit. Care Med.
20011631087-1092 Chest 1999115957-965.
50
Global Initiative for ChronicObstructiveLungDis
ease
Global Initiative for Chronic Obstructive Lung
Disease. Global Strategy for the Diagnosis,
Management, and Prevention of Chronic Obstructive
Pulmonary Disease NHLBI/WHO Workshop Report.
Bethesda, Md National Heart, Lung, and Blood
Institute, National Institutes of Health March
2001. NIH publication 2701A.
51
GOLD Recommendations for ICS Use
Severity
Symptoms
Spirometry
Treatment
At Risk Stage 0
/- Chronic cough, sputum
Normal
Education, avoidance risk factors, flu vaccine
Mild Stage I
FEV1 / FVC lt 70
Short-acting ?2- adrenergic PRN
/- Chronic cough, sputum
FEV1 gt 80 predicted
FEV1 / FVC lt 70 FEV1 30 - 80 predicted
Moderate Stage II A B
Reg Bronchodilator Consider ICS Rehabilitation
/- Chronic cough, sputum, dyspnea
Severe Stage III
/- Cough, sputum, dyspnea
Reg Bronchodilator Consider ICS Rehabilitation LT
Oxygen Surgery
FEV1 / FVC lt 70 FEV1 lt 30 or FEV1 lt 50 with
respiratory failure, cor pulmonale
52
A Physicians Perspective on Treatment of COPD

• Smoking cessation
• Bronchodilator therapy alone is not adequate in
  many patients
• Use of ICS in COPD

53
CONCLUSIONS

• Diagnosis of COPD is based on several clinical
  parameters
• A large proportion of patients with COPD are
  reversible
• Small magnitude of response on efficacy measures
  are usually observed
• Guidelines support use of ICS in patients with
  moderate to severe COPD

54
(No Transcript)
55
Overview ofClinical Program

• Tushar Shah, MDVice PresidentRespiratory
  Clinical Development

56
Topics of Presentation

• Review results of clinical program designed in
  consultation with FDA
• Primary objectives
• FLOVENT DISKUSGreater efficacy compared to
  placebo with no significant safety concerns
• ADVAIR DISKUSGreater efficacy compared to
  fluticasone propionate (FP) and salmeterol alone
  with no significant safety concerns
• Review long-term safety data with FP

57
Definitions

• FSC Fluticasone propionate and Salmeterol
  Combination product
• FSC 500/50 ADVAIR 500
• FSC 250/50 ADVAIR 250

58
Overview of Clinical Program

• FLTA3025 FP 500 24 weeks
• N640 FP 250
• Placebo
• SFCA3006 FSC 500/50 24 weeks
• N691 FP 500
• SAL 50
• Placebo
• SFCA3007 FSC 250/50 24 weeks
• N723 FP 250
• SAL 50
• Placebo

59
Study Design FLTA3025
60
Study Design SFCA3006
FSC 500/50mcg BID (n169)
FP 500mcg BID (n173)
PRNalbuterol
SAL 50mcg BID (n164)
PlaceboRun-in
Placebo BID (n185)
2 weeks
24 weeks
61
Study Design SFCA3007
FSC 250/50mcg BID (n178)
FP 250mcg BID (n183)
PRNalbuterol
SAL 50mcg BID (n177)
PlaceboRun-in
Placebo BID (n185)
2 weeks
24 weeks
62
Key Inclusion Criteria

• COPD as defined by ATS
• Age ?40 years
• Current or ex-smoker (?20 pack years)
• Pre-bronchodilator FEV1 lt65 predicted
• FEV1/FVC ?70
• Dyspnea and symptoms of chronic bronchitis

63
Key Exclusion Criteria

• Current diagnosis of asthma
• Use of systemic corticosteroids or high dose ICS
  for 6 weeks prior toscreening visit
• Need for long-term oxygen therapy
• COPD exacerbation during run-in

64
Primary Efficacy Measures

• Pre-dose FEV1
• FP vs. Placebo
• FSC vs. SAL (contribution of FP)
• 2 hour post-dose FEV1
• FSC vs. FP (contribution of SAL)

65
Secondary Efficacy Measures

• Transition Dyspnea Index (TDI)
• Chronic Respiratory Disease Questionnaire (CRDQ)
• Chronic Bronchitis Symptoms Questionnaire (CBSQ)
• Diary Card (AM PEF, Ventolin use and nighttime
  awakenings)
• Time to first COPD exacerbation

66
Primary Analysis

• Endpoint was used to account for patient
  withdrawals
• Endpoint Last post-baseline observation

67
Patient Demography and Baseline Characteristics
Were Similar Across Treatment Groups

• FSC250/ FSC500/
• Placebo SAL50 FP250 FP500 50 50
• Variable n572 n337 n399 n386 n178 n165
• Age (yrs) 65 64 65 64 63 62
• Gender ( male) 70 61 69 64 61 62
• Race ( white) 94 94 93 94 96 95
• Curr Smoker 48 49 46 47 43 46
• Pack years 63 63 61 60 60 62
• Prev ICS 27 25 29 28 23 28
• FEV1 pred 42 41 41 41 41 41
• BD resp. ( pts rev) 57 53 57 55 56 53
• Emphysema 75 72 73 74 71 75

68
FLOVENTEFFICACY RESULTS
69
FLOVENT

• Primary Efficacy Measure
• Pre-dose FEV1
• FP vs. Placebo

70
FLTA3025 Dose-Related Increases in Pre-Dose FEV1
Were Seen with FP Treatment vs. Placebo

(8)
? FEV1 (ml)
(5)
(2)
Endpoint
P0.010 vs PLA
71
SFCA3006 Significantly Greater Improvement in
Pre-Dose FEV1 Seen with FP500 vs. Placebo

(11)
? FEV1 (ml)
(2)
Endpoint
Plt0.001 vs PLA
72
SFCA3007 Significantly Greater Improvements in
Pre-Dose FEV1 Seen with FP250 vs. Placebo

(11)
? FEV1 (ml)
(1)
Endpoint
Plt0.001 vs PLA
73
SFCA3007 Additional Evidence of Improvements in
Pre-Dose FEV1 with FP250

(17)
(11)
(9)
? FEV1 (ml)
(1)
Endpoint
P0.012 vs SAL
74
Change in Pre-dose FEV1 (mL) for FP at Endpoint
in Reversible/Non-Reversible Patients
75
Greater Improvements Seen for Most Secondary
Efficacy Measures with FP vs Placebo

• FLTA3025 SFCA3007 FLTA3025 SFCA3006
• Measure FP250 FP250 FP500 FP500
• TDI (dyspnea) ?
• CRDQ (QOL) ? ?
• CBSQ (cough/sputum)
• PEF ? ? ? ?
• NT awakenings ? ? ? ?
• Ventolin use ? ? ?
• Time to COPD exac.

• statistically significantly different
  than placebo
• P0.05, FP vs. Placebo
• Pgt0.05, FP vs. Placebo

76
FLOVENT EFFICACY SUMMARY

• Significantly greater improvements in primary
  efficacy measure (pre-dose FEV1)
• Magnitude of improvement related to reversibility
• Secondary efficacy measures supportive
• Suggestion of dose response

77
ADVAIREFFICACY RESULTS
78
ADVAIR

• Primary Efficacy Measure
• Pre-dose FEV1
• FSC vs. SAL (contribution of FP)

79
SFCA3006 Significantly Greater Improvement in
Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

(15)
(10)
? FEV1 (ml)
Endpoint
P0.012 vs SAL
80
SFCA3006 Significantly Greater Improvement in
Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

(15)
(11)
(10)
? FEV1 (ml)
(2)
Endpoint
P0.012 vs SAL
81
SFCA3007 Significantly Greater Improvements in
Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

(17)
(9)
? FEV1 (ml)
Endpoint
P0.012 vs SAL
82
SFCA3007 Significantly Greater Improvements in
Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

(17)
(11)
(9)
? FEV1 (ml)
(1)
Endpoint
P0.012 vs SAL
83
ADVAIR

• Primary Efficacy Measure
• 2 hour post-dose FEV1
• FSC vs. FP (contribution of SAL)

84
SFCA3006 Significantly Greater Improvements in
Post-Dose FEV1 Seen with FSC500/50 vs. FP500

(24)
(13)
? FEV1 (ml)
Endpoint
Plt0.001 vs FP
85
SFCA3006 Significantly Greater Improvements in
Post-Dose FEV1 Seen with FSC500/50 vs. FP500

(24)
(22)
(13)
? FEV1 (ml)
(4)
Endpoint
Plt0.001 vs FP
86
SFCA3007 Significantly Greater Improvements in
Post-Dose FEV1 Seen with FSC250/50 vs. FP250

(27)
(14)
? FEV1 (ml)
Endpoint
Plt0.001 vs FP
87
SFCA3007 Significantly Greater Improvements in
Post-Dose FEV1 Seen with FSC250/50 vs. FP250

(27)
(19)
(14)
? FEV1 (ml)
(6)
Endpoint
Plt0.001 vs FP
88
Change in FEV1 (mL) for FSC at Endpoint in
Reversible/Non-Reversible patients
SFCA3007
SFCA3006
PLA SAL FP FSC250/50 PLA SAL FP FSC500/50 Pre-
dose Rev. -15 141 138 196 -1 132 123 191 Non-Rev.
19 26 74 126 -8 80 93 116 2 hrPost-dose Rev. 46 2
62 179 328 29 287 161 319 Non-Rev. 71 119 107 221
28 175 111 195
89
Similar Improvements Seen in Secondary Efficacy
Measures for FP and SAL vs. PLA

• SFCA3007 SFCA3007 SFCA3006 SFCA3006
• Measure SAL50 FP250 SAL50 FP500
• TDI (dyspnea) ?
• CRDQ (QOL)
• CBSQ (cough/sputum)
• PEF ? ? ? ?
• NT awakenings ? ? ?
• Ventolin use ? ? ?
• Time to COPD exac.

• statistically significantly different
  than placebo
• P0.05, FP vs. Placebo
• Pgt0.05, FP vs. Placebo

90
Greater Improvements Seen for Almost All
Secondary Efficacy Measures with FSC vs. Placebo

• SFCA3007 SFCA3006
• Measure FSC250/50 FSC500/50
• TDI (dyspnea)
• CRDQ (QOL)
• CBSQ (cough/sputum)
• PEF ? ?
• NT awakenings ? ?
• Ventolin use ? ?
• Time to COPD exac

• statistically significantly different
  than placebo
• P0.05, FP vs. Placebo
• Pgt0.05, FP vs. Placebo

91
SFCA3006 Significantly Greater Improvement in
TDI Score Seen with FSC500/50 vs. SAL50 and PLA
,


TDI Score
Endpoint
P0.005 vs PLA Plt0.001 vs SAL
92
Treatment with FSC250/50 Led to Greater Increase
in AM PEF Within 1 Day
,

? PEF (L/min)


Plt0.001 vs PLA Plt0.001 FSC vs FP and SAL
93
ADVAIR EFFICACY SUMMARY

• Significantly greater improvements in both trials
  on the primary efficacy measures
• Advair vs. salmeterol for pre-dose FEV1
• Advair vs. FP for 2-hour post-dose FEV1
• Magnitude of improvement related to reversibility
• Secondary efficacy measures supportive
• Advair 250/50 and 500/50 provide similar benefits

94
SAFETY RESULTSFlovent / Advair
95
Safety Exposure

• 2,054 Patients in clinical program
• 790 on FP
• 347 on Advair
• Additional safety from 1298 COPD patients from
  non US studiesevaluating FP
• Supported by extensive safety in asthma

96
Adverse Events Occurred at Similar Frequency
Across Treatment Groups

• PLA SAL50 FP250 FP500 FSC250/50
  FSC500/50 n576 n341 n399 n391 n178 n169
• Mean Exposure 129 139 136 132 141 138 (days)
• Patients with 69 68 74 80 70 78AE ()
• Patients withdrawn 6 4 6 11 5 7due to AE ()
• Patients with 6 4 6 7 4 5SAE ()
• Deaths 4 0 0 0 0 0

97
Similar Adverse Events of Special Interest Except
for Expected Topical Effects of ICS
PLA SAL50 FP250 FP500 FSC250/50 FSC500/50 Adver
se Events n576 n341 n399 n391 n178 n169 Can
didiasis 1 2 7 13 11 11 Throat
Irritation 6 7 9 9 8 11 Hoarseness
/ 1 lt1 5 5 5 3Dysphonia Fractures 2 lt1 1
1 2 2 Cataracts lt1 0 0 lt1 0 0 Ocular
Pressure lt1 0 0 0 0 1Disorders
98
Comparable Incidence of Pneumonia Across
Treatment Groups
PLA SAL50 FP250 FP500 FSC250/50 FSC500/50 Pneum
onia n576 n341 n399 n391 n178 n169 Adverse
Events 7 2 7 10 0 2 (1.2) (0.6)
(1.8) (2.6) (1.2) Serious Adverse 3
2 5 7 0 2Events (0.5) (0.6) (1.3)
(1.8) (1.2)
99
HPA Axis Monitoring(Performed in a Subset of
Patients)

• 12 hour unstimulated cortisol profile in FLTA3025
  (n86)
• In SFCA3006 and SFCA3007 (n359)
• Morning cortisol concentrations
• Short ACTH stimulation test

100
No Clinically Significant Difference in HPA Axis
Results Between FSC and Individual Agents or
Placebo

• 12 hour unstimulated plasma cortisol profile
• FP250 10 lt placebo (N.S.)
• FP500 21 lt placebo (plt0.05)
• The incidence of abnormal morning cortisol was
  similar across all treatment groups
• The incidence of abnormal short ACTH stimulation
  tests was similar across all treatment groups

101
SUMMARY OF SAFETY RESULTS

• Flovent Diskus
• Flovent was well tolerated
• No clinically relevant safety concerns identified
  compared to placebo
• Advair Diskus
• Advair was well tolerated
• No difference in safety results between Advair
  and individual agents and/or placebo

102
Long-term Safety Data with FP

• Comparison of systemic exposure between patients
  with asthma and COPD
• Clinical studies examining bone mineral density
  and ophthalmic effects in patients with asthma
• Incidence of fractures and ophthalmic AEs in a 3
  year clinical study in patients with COPD

103
The Range of Systemic Exposure with FP Diskus in
COPD is Not Greater Than FP CFC MDI in Asthma
Diskus 500mcg BID CFC MDI 440mcg BID
FP AUClast (pgh/mL)
Asthma
COPD
104
Clinical Studies Examining BMD and/or Ophthalmic
Effects of FP inPatients with Asthma

• Two 2-year safety studies of FP vs placebo
• FP 88mcg, FP 440mcg CFC MDI BID (FLTA3001)
• FP 500mcg ROTADISK BID (FLTA3017)
• Comparator MDI studies
• FP versus BDP (3 trials)
• FP versus budesonide (2 trials)

105
Mean Percent Change in Lumbar Spine BMD was
Similar Between FP Groups Compared to Placebo
Mean Percent Change from Baseline
Weeks
Data on File, GlaxoSmithKline (FLTA3001).
106
No Evidence of Cataracts orGlaucoma was Seen
with FP versus Placebo Treatment

• No posterior subcapsular cataracts
• No diagnosis of glaucoma

107
BMD Results from Clinical Trials Comparing FP MDI
vs. Other ICS

• Treatment Groups
• (mcg BID) BMD Results Reference
• FP 250, 375, or 500 FP ? at all BMD sites
  assessed Pauwels, 1998
• versus BDP ? at femoral neck trochanter
• BDP 500, 750, or 1000 Wards triangle
• FP 500 versus BDP 1000 FP No vertebral
  trabecular bone decline Egan, 1999
• BDP ? Vertebral trabecular bone
• FP and BDP ? at spine femoral neck
• FP 200 versus BDP 400 FP ? at lumbar
  spine Medici, 2000
• FP 375 versus BDP 750 BDP ? at lumbar spine
• FP 500 versus BUD 800 FP and BUD ? at lumbar
  spine trochanter Hughes, 1999
• FP ? at femoral neck
• BUD ? at femoral neck
• FP 250 versus BUD 400 FP and BUD ? at all BMD
  sites assessed Harmanci, 1999

108
ISOLDE Adverse Events of Special Interest
Placebo BID FP500mcg BID n370 n372 Mean
Exposure (days) 748 824 Adverse
Events Fractures 17 (5) 9 (2) Cataracts 7
(2) 5 (1) Ocular Pressure Disorders 3
(lt1) 6 (2) Serious Adverse Events Fractures
7 (2) 4 (1)
109
SummaryLong-term Safety Data with FP

• Exposure data allows extrapolation of safety data
  from asthma to COPD
• Two 2-year placebo controlled FP studies showed
  no clinically relevant BMD or eye findings
• FP vs BDP studies suggest not all ICS may have
  same predisposition to effect BMD
• No evidence of increased incidence of fractures
  and ophthalmic AEs over 3 years of FP treatment
  in COPD

110
Proposed Dosage and Administration Recommendations

• For Flovent Diskus The starting dosage is 250mcg
  twice daily
• For Advair Diskus The starting dosage is
  250/50mcg twice daily
• For patients who do not respond adequately to
  the starting dose, increasing the dose to 500mcg
  for Flovent and 500/50 for Advair twice daily may
  provide additional control.

111
CONCLUSIONS

• Clinical programs achieved regulatory objectives
• Flovent greater improvement in primary efficacy
  measure with no safety issues
• Advair superiority over individual components in
  primary efficacy measures with a similar safety
  profile
• Long-term safety data provide further reassurance
  on the use of FP in treatment of COPD

112
(No Transcript)
113
Summary Remarks

• David Wheadon, MD
• Senior Vice President, Regulatory Affairs
• GlaxoSmithKline

114
COPD is a Significant Public Health Problem in
the US
Proportion of 1965 Mortality Rate
3.0
Coronary Heart Disease
Stroke
Other CVD
COPD
All Other Causes
2.5
2.0
1.5
1.0
0.5
59
64
35
163
7
0
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
1965 - 1998
115
Current Therapeutic Managementof COPD

• COPD remains under diagnosed and under treated
• Bronchodilators are the only approved treatments
• Additional treatment options are needed

116
Combined Effects of Salmeterol and FP in COPD
Salmeterol FP
?
Airway Obstruction
StructuralChanges
Inflammation
Increased Neutrophils,macrophages, CD8
lymphocytes. Elevated IL-8, TNFa? Protease/anti-pr
oteaseimbalance
Smooth muscle contraction Increased cholinergic
tone Loss of elastic recoil
Alveolar destruction Collagen deposition Glandular
hypertrophy Airway fibrosis

• ? Symptoms
• ? FEV1
• ? Exacerbations

117
Advair Diskus / Flovent Diskus

• Achieved objectives of clinical program
• Flovent provided superior efficacy over placebo
  for primary measure
• Advair provided superior efficacy over individual
  agents for primary measures
• No significant safety issues identified

118
Pulmonary - Allergy Drugs Advisory Committee
Meeting

• January 17, 2002
• FLOVENT DISKUS NDA 20-833
• ADVAIR DISKUS NDA 21-077

119
External Experts

• Professor Romain Pauwels, M.D.
• Professor of Respiratory Medicine at University
  of Gent, Belgium
• Jonathon D Adachi, M.D.
• Professor of Medicine at McMaster University,
  Hamilton, Ontario

120
(No Transcript)